Submissions for variant NM_000642.3(AGL):c.1384del (p.Trp461_Val462insTer)

dbSNP: rs786204678

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169486	SCV000220939	likely pathogenic	Glycogen storage disease type III	2014-12-09	criteria provided, single submitter	literature only
Invitae	RCV000169486	SCV000818823	pathogenic	Glycogen storage disease type III	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val462*) in the AGL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AGL are known to be pathogenic (PMID: 19299494). This variant is present in population databases (rs786204678, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with glycogen storage disease, type III (GSD III) (PMID: 20648714). ClinVar contains an entry for this variant (Variation ID: 189080). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169486	SCV000916429	pathogenic	Glycogen storage disease type III	2018-11-30	criteria provided, single submitter	clinical testing	Variant summary: AGL c.1384delG (p.Val462X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. p.Trp680X, p.Arg864X, p.Arg977X). The variant allele was found at a frequency of 4.1e-06 in 245906 control chromosomes (gnomAD). c.1384delG has been reported in the literature in homozygous individuals affected with Glycogen Storage Disease Type III (Golstein_2010). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000169486	SCV002055477	pathogenic	Glycogen storage disease type III	2021-07-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000169486	SCV002783930	pathogenic	Glycogen storage disease type III	2021-07-26	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000169486	SCV003761286	pathogenic	Glycogen storage disease type III	2023-01-25	criteria provided, single submitter	curation	The homozygous p.Trp461_Val462insTer variant in AGL was identified by our study in one individual with congenital myopathy (Broad Institute Rare Genomes Project). The p.Trp461_Val462insTer variant in AGL has been previously reported in 3 unrelated individuals with glycogen storage disease type III (PMID: 34649782, PMID: 20648714) but has been identified in 0.002% (1/34582) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1383849192). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. These three affected individuals (PMID: 34649782, PMID: 20648714) were homozygotes, which increases the likelihood that the p.Trp461_Val462insTer variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 189080) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 461 and leads to a premature termination codon 1 amino acid downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the AGL gene is an established disease mechanism in autosomal recessive glycogen storage disease type III. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive glycogen storage disease type III. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3 (Richards 2015).
Baylor Genetics	RCV000169486	SCV004212937	pathogenic	Glycogen storage disease type III	2023-07-06	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000169486	SCV001454507	pathogenic	Glycogen storage disease type III	2020-09-16	no assertion criteria provided	clinical testing